EP1881950A1 - Nouveaux composes i - Google Patents

Nouveaux composes i

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Publication number
EP1881950A1
EP1881950A1 EP06733400A EP06733400A EP1881950A1 EP 1881950 A1 EP1881950 A1 EP 1881950A1 EP 06733400 A EP06733400 A EP 06733400A EP 06733400 A EP06733400 A EP 06733400A EP 1881950 A1 EP1881950 A1 EP 1881950A1
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EP
European Patent Office
Prior art keywords
alkyl
compounds
formula
compound
hydrogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP06733400A
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German (de)
English (en)
Inventor
Catrin Jonasson
Håkan MOLIN
Didier Rotticci
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AstraZeneca AB
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AstraZeneca AB
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Publication of EP1881950A1 publication Critical patent/EP1881950A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/56—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and doubly-bound oxygen atoms bound to the carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/84—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/205—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring the aromatic ring being a non-condensed ring
    • C07C43/2055—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring the aromatic ring being a non-condensed ring containing more than one ether bond

Definitions

  • the present invention relates to new compounds of formula I, as a free acid and/orbase or a pharmaceutically acceptable salt, solvate or solvate of salt thereof.
  • the present invention also relates to use of such compounds in therapy, and also pharmaceutical formulations containing such compounds.
  • the present invention further relates to a process for the preparation of compounds of formula I. 0
  • the inhibitory glycine receptors are ion channels belonging to the cys-loop ligand- gated ion channel family. They are pentameric structures composed of two types of membrane spanning subunits ( ⁇ and ⁇ ) forming a pore that is permeable to anions. The sub- s units have four transmembrane domains and a large extracellular N-terminus.
  • ⁇ 4 (Harvey, et al, European Journal of Neuroscience 12, 994-1001. 2000)) and one ⁇ subunit (Pfeiffer and Betz, 1981), (Pfeiffer et al., 1982) have been identified.
  • AU subunits except ⁇ 4 do appear to exist in humans.
  • the predominant receptor isoform consists of ⁇ l-and ⁇ -subunits with a possible stoichiometry 3 ⁇ 2 ⁇ .
  • homo-oligomeric ⁇ -subunits (homomeric s GIyR ⁇ l) function efficiently with functional properties similar to those of native receptors.
  • GIyRs are located at postsynaptic membranes mainly in the spinal cord and brain stem (Rajendra, S, J W Lynch, P R Schofield. Pharmacology & Therapeutics 73, 121-46. 1997); 0 (Laube, B, G Maksay, R Schemm, H Betz. Trends in Pharmacological Sciences 23, 519- 527. 2002). Glycinergic neurons in the dorsal horn receive a major input from myelinated low-threshold mechanoreceptive primary (A ⁇ ) afferents. Binding of an agonist induces rapid opening of the channel and allowing an influx of Cl- into the cytoplasm.
  • a ⁇ myelinated low-threshold mechanoreceptive primary
  • mice deficient in GIyR ⁇ 3 show a reduction in pain sensiti- sation induced by spinal PGE2 injection or peripheral inflammation.
  • GIyR ⁇ 3 deficient mice do also lack PGE2 induced inhibition of glycinergic neurotransmission (Harvey, RJ, U B Depner, H Wassle,. S Ahmadi, C Heindl, H Reinold, T G Smart, K Harvey , B Schutz, 20 O M Abo-Salem, A Zimmer, P Poisbeau, H Welzl, D P Wolfer, H Betz, H U Zeilhofer, U Muller. Science 304, 884-887. 2004).
  • Positive modulators or agonists of GIyR could be therapeutically beneficial in all conditions with impaired inhibitory tone, specifically as analgesics in neuropathic or inflamma-
  • 25 tory pain syndromes such as painful diabetic neuropathy, post traumatic neuralgia, post herpetic neuralgia, trigeminal neuralgia, arthritis, rheumatoid diseases, fibromyalgia, low back pain with radiculopathy and post-operative pain.
  • pain syndromes such as painful diabetic neuropathy, post traumatic neuralgia, post herpetic neuralgia, trigeminal neuralgia, arthritis, rheumatoid diseases, fibromyalgia, low back pain with radiculopathy and post-operative pain.
  • pain syndromes such as painful diabetic neuropathy, post traumatic neuralgia, post herpetic neuralgia, trigeminal neuralgia, arthritis, rheumatoid diseases, fibromyalgia, low back pain with radiculopathy and post-operative pain.
  • pain associated with various conditions including angina, renal or billiary colic, menstruation, migraine and gout, stroke, head trauma,
  • GIyR agonists or positive modulators could also be used as anticonvulsants and muscle-relaxants as well as anti-inflammatory agents.
  • Glycine receptors are also involved in the acrosome reaction (AR) and activation of GIyRs seems to be essential for the AR to occur.
  • GIyR agonists or positive modulators could therefore be useful as fertility enhancers or as a male contraceptive.
  • Glycine receptors are also expressed in the auditory pathways and in the retina.
  • GIyR positive modulators or agonists could therefore be used in the treatment of auditory neuropathic disorders such as tinnitus and opMialmological disorders such as retinopathies, diabetic retinopathies and glaucoma (Lynch, JW. Physiol. Rev. 84, 1051-1095. 2004).
  • Glycine receptor subunits have also been identified in the nucleus accumbens and GIyR selective compounds have been suggested to combat psychiatric disorders, in which the mesolimbic dopamine system is implicated, such as alcoholism, drug addiction and psychosis (Molander, A, B S ⁇ derpalm. Alcoholism: Clinical and Experimental Research 29, 17-26. 2005).
  • Prostaglandins and leukotrienes are produced by the activity of three enzymes; cyclooxy- genase-1, cyclooxygenase-2 (COX-I and COX-2) and 5-lipoxygenase (5-LOX), as part of the arachidonic acid (AA) pathway.
  • COX-I converts AA to e.g. prostaglandins such as PGD2, PGE2, PGF2 and PGI2 (prostacyclin) and thromboxanes such as TXA2.
  • COX-2 converts AA to a narrower range of prostaglandins, specifically PGE2 and PGI2.
  • 5-LOX together with other enzymes converts AA to leukotrienes (LTB4, LTC4, LTD4 and LTE4).
  • the products from the AA pathway play a major role in human physiology that includes renal homeostasis, gastroprotection, vascular homeostasis and pathophysiological processes, such as pain and inflammation.
  • PGE2 and PGI2 have various physiological and pathophysiological effects. For example they have potent effects on vasodilatation and vascular permeability.
  • Inhibitors of cyclooxygenases have been developed as anti-inflammatory drugs as have inhibitors of 5-lipoxygenase.
  • Dual COX/LOX inhibitors are in the clinic for evaluation of inflammation related diseases, such as rheumatoid arthritis and osteoarthritis as well as pneumological diseases. They could also be used in artbrosclerosis and stroke. Further they could be used as antihypertensive agents (Simmons, DL, Botting Regina M., T HIa. Pharmacol Rev 56, 387-487. 2004), (Bertolini, A, A Ottani, Sandrini M. Current Medicinal Chemistry 9, 1033-1043. 2002). SUMMARY OF THE INVENTION
  • the object of the present invention is thus to provide new positive modulators and/or agonists of GIyR, that are optionally also COX and/or LOX inhibitors.
  • X is selected from hydrogen, halo, -CN, -CONH 2 , -CON(C 1-6 alkyl)H, -CON(C 1-6 alkyl) 2 and heterocyclic groups;
  • Rl is selected from C 1-6 alkyl and Cs- ⁇ cycloalkyl;
  • Z is -OH
  • M is selected from -C(O)-, -CH(OR 3 )-, -N(R a )-, and -S(OV, wherein R a is hydrogen or C 1-6 alkyl and r is 0, 1 or 2,
  • R2 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, heterocycloalkyl, aryl, alkylaryl, and heteroaryl,
  • R2 is substituted with halo, -NO 2 , -CN 1 -OH, -CF 3 , -OCF 3 , -NH 2 , and/or -CONH 2 , when Y is -Ci- ⁇ alkyl; or
  • Z is -Ci- ⁇ alkoxy, M is bond,
  • R2 is selected from C 1-6 alkyl, C 3-6 CyClOaIlCyI, heterocycloalkyl, aryl, alkylaryl, and heteroaryl, when Y is -d-ealkoxy.
  • X is selected from hydrogen, halo, -CN, -CONH 2 , -CON(C 1-6 alkyl)H 5 -CON(C 1-6 alkyl) 2 and heterocyclic groups;
  • Rl is selected from Ci- ⁇ alkyl and C 3-6 cycloalkyl; whereby Z is -OH,
  • M is selected from -C(O)-, -CH(OR 3 )-, -N(R 3 )-, and -S(0) r , wherein R a is hydrogen or Ci-galkyl and r is O, 1 or 2,
  • R2 is selected from C 1 ⁇ aIkVl, C 3-6 cycloalkyl, heterocycloalkyl, aryl, alkylaryl, and heteroaryl, R2 is substituted with halo, -NO 2 , -CN, -OH, -CF 3 , -OCF 3 , -NH 2 , and/or -CONH 2 , when Y is -C 1-6 alkyl; or
  • Z is -C 1-6 alkoxy
  • M is bond
  • R2 is selected from Ci -6 alkyl, C 3-6 Cycloalkyl, heterocycloalkyl, aryl, alkylaryl, and heteroaryl, when Y is -Ci -6 alkoxy, for use in therapy.
  • neuropathic or inflammatory pain syndromes such as painful diabetic neuropathy, post traumatic neuralgia, post herpetic neuralgia, trigeminal neuralgia, arthritis, rheumatoid diseases, fibromyalgia, low back pain with radiculopathy and post-operative pain; pain associated with angina, renal or Miliary colic, menstruation, migraine and gout, stroke, head trauma, anoxic and ischemic injuries, hypoglycaemia, cardiovascular diseases and/or cancer; auditory neuropathic disorders such as tinnitus; ophthalmological disorders such as retinopathies, diabetic retinopathies or glaucoma; and/or psychiatric disorders, such as alcoholism, drug addiction and psychosis.
  • neuropathic or inflammatory pain syndromes such as painful diabetic neuropathy, post traumatic neuralgia, post herpetic neuralgia, trigeminal neuralgia, arthritis, rheumatoid diseases,
  • a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula I in association with one or more pharmaceutically acceptable diluent, excipients and/or inert carrier, especially for the treatment of neuropathic or inflammatory pain syndromes such as painful diabetic neuropathy, post traumatic neuralgia, post herpetic neuralgia, trigeminal neuralgia, arthritis, rheumatoid diseases, fibromyalgia, low back pain with radiculopathy and post-operative pain; pain associated with angina, renal or billiary colic, menstruation, migraine and gout, stroke, head trauma, anoxic and ischemic injuries, hypoglycaemia, cardiovascular diseases and/or cancer; auditory neuropathic disorders such as tinnitus; ophthalmological disorders such as retinopathies, diabetic retinopathies or glaucoma; and/or psychiatric disorders, such as alcoholism, drug addiction and psychos
  • Another aspect of the invention relates to the use of the compound according formula I in the manufacture of a medicament for the treatment of neuropathic or inflammatory pain syndromes such as painful diabetic neuropathy, post traumatic neuralgia, post herpetic neuralgia, trigeminal neuralgia, arthritis, rheumatoid diseases, fibromyalgia, low back pain with radiculopathy and post-operative pain; pain associated with angina, renal or billiary colic, menstruation, migraine and gout, stroke, head trauma, anoxic and ischemic injuries, hypoglycaemia, cardiovascular diseases and/or cancer; auditory neuropathic disorders such as tinnitus; ophthalmological disorders such as retinopathies, diabetic retinopathies or glaucoma; and/or psychiatric disorders, such as alcoholism, drug addiction and psychosis.
  • neuropathic or inflammatory pain syndromes such as painful diabetic neuropathy, post traumatic neuralgia, post herp
  • neuropathic or inflammatory pain syndromes such as painful diabetic neuropathy, post traumatic neuralgia, post herpetic neuralgia, trigeminal neuralgia, arthritis, rheumatoid diseases, fibromyalgia, low back pain with radiculopathy and post-operative pain; pain asso- ciated with angina, renal or Miliary colic, menstruation, migraine and gout, stroke, head trauma, anoxic and ischemic injuries, hypoglycaemia, cardiovascular diseases and/or cancer; auditory neuropathic disorders such as tinnitus; ophthalmological disorders such as retinopathies, diabetic retinopathies or glaucoma; and/or psychiatric disorders, such as al- coholism, drug addiction and psychosis, comprising administering to a mammal, including man, in need of such treatment, a therapeutically effective amount of the compound according formula I.
  • C m-n or "C m-n group” used alone or as a prefix, refers to any group having m to n carbon atoms.
  • Cj -6 ' means a carbon group having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • heteroatom refers to an atom which is not carbon or hydrogen.
  • heteroatoms include but are not limited to nitrogen, oxygen, and sulfur.
  • alkyl includes both straight and branched chain alkyl groups.
  • C ⁇ aHcyl means an alkyl group having 1 to 6 carbon atoms and may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t- butyl, n-pentyl, i-pentyl, t-pentyl, neo-pentyl, n-hexyl, i-hexyl, or t-hexyl.
  • alkoxy includes both straight or branched alkoxy groups.
  • Cr 6 alkoxy may be, but is not limited to, methoxy, ethoxy, n-pro- poxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, n-pentoxy, i-pentoxy, t-pentoxy, neo-pentoxy, n-hexoxy, i-hexoxy, or t-hexoxy.
  • aryl includes both aromatic mono- cyclic and bicyclic systems containing from 5 to 10 carbon atoms; in the case of a bicyclic system, at least one of the rings is of aromatic character, while the other ring may be aromatic or partially hydrogenated.
  • Non-limiting examples of the term “aryl” are phenyl, naphthyl, indenyl, and tetralinyl.
  • alkylaryl means an aryl group having one or more alkyl groups pendant therefrom.
  • alkylaryl are benzyl, ethylnaphthyl, propylindenyl, and butyltetralinyl
  • heteroaryl includes aryl groups as described above in which 1 to 4 carbon atoms are replaced by 1 to 4 hetero atoms, identical or different, selected independently of each other from oxygen, sulfur and nitrogen.
  • heteroaryl are furyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl or thienyl.
  • cycloalkyl includes both mono- cyclic and polycyclic systems containing from 3 to 10 carbon atoms, the systems being saturated or partially unsaturated but without aromatic character and it being understood that in the case of a polycyclic system one or more of the cycle(s) could be fused together or form a link.
  • C 3-6 cycloalkyl is meant a cycloalkyl group containing from 3 to 6 carbon atoms, and may be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • a “heterocyclic group” is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 4-12 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a -CH 2 - group can optionally be replaced by a -C(O)- and a ring sulphur atom may be optionally oxidised to form the S-oxide(s).
  • heterocyclic group are morpholino, piperidyl, pyridyl, pyranyl, pyrrolyl, isothiazolyl, indolyl, quinolyl, thienyl, 1,3-benzodioxolyl, thiadiazolyl, piperazinyl, thiazolidinyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl, 3,5- dioxapiperidinyl, tetrahydropyranyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl, isoxazolyl, 4-pyridone, 1-isoquinolone, 2-pyrrolidone and 4-thiazolidone.
  • heterocycloalkyl includes cycloalkyl groups as defined hereinbefore in which 1 to 4 carbon atoms are replaced by 1 to 4 heteroatoms.
  • Non-limiting examples of the term “heterocycloalkyl” are tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, morpholine, thiomorpholine, tetrahydropyran, tetrahydrothiopyran.
  • X may be independently selected from hydrogen, halo, -CN, -CONH 2 , and heterocyclic groups.
  • X may be independently selected from hydrogen, -Br, -CN, -CONH 2 , and tetrazolyl.
  • Rl is C 3-4 alkyl.
  • Z is -OH
  • M is -C(O)-
  • R2 is selected from C 1-6 alkyl, C3 -6 cycloalkyl, heterocycloalkyl, aryl, alkylaryl, and heteroaryl
  • R2 is substituted with halo, -NO 2 , -CN, -OH, -CF 3 , -OCF 3 , -NH 2 , and/or -CONH 2
  • Y is -C 1-6 alkyl.
  • R2 is aryl.
  • R2 may be independently selected from phenyl, naphthyl, cyclohexyl, me- thylbenzyl, and quinoxalinyl.
  • Z is -OH
  • M is selected from -C(O)-, -CH(0R a )-, -N(R a )-, and -S(O) 1 -, wherein R a is hydrogen or C 1-6 alkyl and r is O, 1 or 2, R2 is selected from C 1-6 alkyl, C 3- 6cycloalkyl, heterocycloalkyl, aryl, alkylaryl, and heteroaryl, R2 is substituted with halo, particularly chloro, and Y is -Q ⁇ alkyl.
  • X is selected from hydrogen, -Br, -CN, -CONH 2 , and tetrazolyl;
  • Y is -CH 3 ;
  • Rl is C 3-4 alkyl;
  • M is -C(O)-;
  • R2 is selected from phenyl, naphthyl, cyclohexyl, methylbenzyl, and quinoxalinyl; R2 is substituted with chloro; and Z is -OH.
  • X is selected from hydrogen, -Br, -CN, -CONH 2 , and tetrazolyl; Y is -OCH 3 ; Rl is C 3-4 alkyl; M is a bond; R2 is selected from phenyl, naphthyl, cyclohexyl, methylbenzyl, and quinoxalinyl; and Z is -OCH 3 .
  • compounds said compounds being:
  • a suitable pharmaceutically acceptable salt of the compound of the invention is, for example, an acid-addition salt, for example an inorganic or organic acid.
  • a suitable pharmaceutically acceptable salt of the compounds of the invention is an alkali metal salt, an alkaline earth metal salt or a salt with an organic base that affords a physiologically-acceptable cation.
  • Some compounds of formula I may have chiral centres and/or geometric isomeric centres (E- and Z- isomers), and it is to be understood that the invention encompasses all such optical, diastereoisomers and geometric isomers.
  • the present invention relates to the use of compounds of formula I as hereinbefore defined as well as to the salts thereof.
  • Salts for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formula I.
  • a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of the compound of formula I, or salts, solvates or solvated salts thereof, in association with one or more pharmaceutically acceptable diluent, excipients and/or inert carrier.
  • the composition may be in a form suitable for oral administration, for example as a tablet, pill, syrup, powder, granule or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) as a sterile solution, suspension or s emulsion, for topical administration e.g. as an ointment, patch or cream or for rectal administration e.g. as a suppository.
  • compositions may be prepared in a conventional manner using one or more conventional excipients, pharmaceutical acceptable diluents and/or inert carriers.
  • Suitable daily doses of the compounds of formula I in the treatment of a mammal, including man are approximately 0.01 to 250 mg/kg bodyweight at peroral administration and about 0.001 to 250 mg/kg bodyweight at parenteral administration.
  • the typical daily dose of the active ingredients varies within a wide range and will depend on various factors such as the relevant indication, severity of the illness being treated, the route of administration, s the age, weight and sex of the patient and the particular compound being used, and may be determined by a physician.
  • the compounds of the present invention are expected to be useful in the treatment of 0 neuropathic or inflammatory pain syndromes such as painful diabetic neuropathy, post traumatic neuralgia, post herpetic neuralgia, trigeminal neuralgia, arthritis, rheumatoid diseases, fibromyalgia, low back pain with radiculopathy and postoperative pain; pain associated with angina, renal or billiary colic, menstruation, migraine and gout, stroke, head trauma, anoxic and ischemic injuries, s hypoglycaemia, cardiovascular diseases and/or cancer; auditory neuropathic disorders such as tinnitus; ophthalmological disorders such as retinopathies, diabetic retinopathies or glaucoma; and/or psychiatric disorders, such as alcoholism, drug addiction and psychosis.
  • painful diabetic neuropathy post traumatic neuralgia, post herpetic neuralgia, trigeminal neuralgia, arthritis, rheuma
  • the invention relates to compounds of formula I as defined hereinbefore, for use in therapy.
  • the invention relates to compounds of formula I as defined hereinbefore, for use in treatment of neuropathic or inflammatory pain syndromes such as painful diabetic neuropathy, post traumatic neuralgia, post herpetic neuralgia, trigeminal neuralgia, arthritis, rheumatoid diseases, fibromyalgia, low back pain with radiculopathy and post- operative pain; pain associated with angina, renal or billiary colic, menstruation, migraine and gout, stroke, head trauma, anoxic and ischemic injuries, hypoglycaemia, cardiovascular diseases and/or cancer; auditory neuropathic disorders such as tinnitus; ophthalmological disorders such as retinopathies, diabetic retinopathies or glaucoma; and/or psychiatric disorders, such as alcoholism, drug addiction and psychosis.
  • neuropathic or inflammatory pain syndromes such as painful
  • the present invention relates also to the use of a compound of formula I as defined hereinbefore, in the manufacture of a medicament for the treatment of neuropathic or inflammatory pain syndromes such as painful diabetic neuropathy, post traumatic neuralgia, post herpetic neuralgia, trigeminal neuralgia, arthritis, rheumatoid diseases, fibromyalgia, low back pain with radiculopathy and post-operative pain; pain associated with angina, renal or billiary colic, menstruation, migraine and gout, stroke, head trauma, anoxic and ischemic injuries, hypoglycaemia, cardiovascular diseases and/or cancer; auditory neuropathic disorders such as tinnitus; ophthalmological disorders such as retinopathies, diabetic retinopathies or glaucoma; and/or psychiatric disorders, such as alcoholism, drug addiction and psychosis.
  • neuropathic or inflammatory pain syndromes such as painful diabetic neuropathy, post traumatic neuralg
  • One embodiment of the invention relates to the use of a compound according to formula I in the treatment of acute and chronic neuropathic pain.
  • the invention also provides a method of treatment of neuropathic or inflammatory pain syndromes such as painful diabetic neuropathy, post traumatic neuralgia, post herpetic neuralgia, trigeminal neuralgia, arthritis, rheumatoid diseases, fibromyalgia, low back pain with radiculopathy and post-operative pain; pain associated with angina, renal or billiary colic, menstruation, migraine and gout, stroke, head trauma, anoxic and ischemic injuries, hypoglycaemia, cardiovascular diseases and/or cancer; auditory neuropathic disorders such as tinnitus; ophthalmological disorders such as retinopathies, diabetic retinopathies or glaucoma; and/or psychiatric disorders, such as alcoholism, drug addiction and psychosis.
  • Another embodiment of the invention relates to the use of a compound according to formula I, for the manufacture of a medicament for acute and chronic neuropathic pain
  • the dose required for the therapeutic or preventive treatment of a particular disorder will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated.
  • the term “therapy” and “treatment” includes prevention and/or prophylaxis, unless there are specific indications to the contrary.
  • the terms “therapeutic” and “therapeutically” should be construed accordingly.
  • the compounds of formula I, or salts, sol- vates or solvated salts thereof are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of neuropathic or inflammatory pain syndromes such as painful diabetic neuropathy, post traumatic neuralgia, post herpetic neuralgia, trigeminal neuralgia, arthritis, rheumatoid diseases, fibromyalgia, low back pain with radiculopathy and post-operative pain; pain asso- ciated with angina, renal or Miliary colic, menstruation, migraine and gout, stroke, head trauma, anoxic and ischemic injuries, hypoglycaemia, cardiovascular diseases and/or cancer; auditory neuropathic disorders such as tinnitus; ophthalmological disorders such as retinopathies, diabetic retinopathies or glaucoma; and/or psychiatric disorders, such as
  • Another aspect of the present invention provides processes for preparing compounds of formula I, or salts, solvates or solvated salts thereof. Processes for the preparation of the compounds in the present invention are described herein. Throughout the following description of such processes it is to be understood that, where appropriate, suitable protecting groups will be added to, and subsequently removed from, the various reactants and intermediates in a manner that will be readily understood by one skilled in the art of organic synthesis. Conventional procedures for using such protecting groups as well as examples of suitable protecting groups are described, for example, in "Protective Groups in Organic Synthesis", T.W. Green, P.G.M. Wuts, Wiley-Interscience, New York, (1999).
  • a transformation of a group or substitu- ent into another group or substituent by chemical manipulation can be conducted on any intermediate or final product on the synthetic path toward the final product, in which the possible type of transformation is limited only by inherent incompatibility of other functionalities carried by the molecule at that stage to the conditions or reagents employed in the transformation.
  • Such inherent incompatibilities, and ways to circumvent them by car- rying out appropriate transformations and synthetic steps in a suitable order will be readily understood to the one skilled in the art of organic synthesis. Examples of transformations are given below, and it is to be understood that the described transformations are not limited only to the generic groups or substituents for which the transformations are exemplified.
  • a process for preparing a compound of formula I, wherein X, Y, Z, Rl, and R2 are, unless specified otherwise, defined as in formula I, comprises of: a)
  • the reaction is performed in a suitable solvent such as dichloromethane, dichloroethane, nitromethane, and advantageously in the presence of a Lewis acid such as for example AlCl 3 , AlBr 3 , Al(OR) 3 , BF 3 , BCl 3 , BBr 3 , ZnCl 2 , FeCl 3 , FeBr 3 ;
  • a Lewis acid such as for example AlCl 3 , AlBr 3 , Al(OR) 3 , BF 3 , BCl 3 , BBr 3 , ZnCl 2 , FeCl 3 , FeBr 3 ;
  • n 0, 1 or 2
  • o 0, 1 or 2
  • W is a halogen such as for example Cl, Br or F.
  • n 0 or 1
  • the product from the first step can be oxidized by treatment with an oxidation reagent such as for example m-Chloroperbenzoic acid, hydrogen peroxide, NaIO 4 , KMnO 4 , PhICl 2 or t-BuOCl.
  • a suitable solvent such as dichloromethane, dichloroethane, THF, DMF
  • a Lewis acid such as for example AlCl 3 , AlBr 3 , Al(OR) 3 , BF 3 , BCl 3 , BBr 3 , ZnCl 2 , FeCl 3 , or FeBr 3
  • a base such as for example pyridine
  • potassium iodide can preferably be used as an additive.
  • the reaction is preferably conducted in the presence of a suitable base such as, for example, sodium carbonate or potassium carbonate, potas- sium fluoride, potassium phosphate, pyridine, 4-dimethylamino-pyridine, triethylamine or morpholine, and conveniently at a temperature in the range, for example 10 to 250°C, preferably in the range 60 to 120°C.
  • a suitable base such as, for example, sodium carbonate or potassium carbonate, potas- sium fluoride, potassium phosphate, pyridine, 4-dimethylamino-pyridine, triethylamine or morpholine, and conveniently at a temperature in the range, for example 10 to 250°C, preferably in the range 60 to 120°C.
  • potassium iodide can optionally be used as an additive.
  • the reaction is preferably conducted in the presence of a suitable base such as, for example, sodium carbonate or potassium carbonate, potassium fluoride, potassium phosphate, pyridine, 4-dimethylaminopyridine, triethylamine or morpholine, and conveniently at a temperature in the range, for example 10 to 250 0 C, preferably in the range 60 to 12O 0 C. d)
  • a suitable base such as, for example, sodium carbonate or potassium carbonate, potassium fluoride, potassium phosphate, pyridine, 4-dimethylaminopyridine, triethylamine or morpholine, and conveniently at a temperature in the range, for example 10 to 250 0 C, preferably in the range 60 to 12O 0 C.
  • the product from the first step can then optionally be oxidized by treatment with an oxidation reagent such as for example m-Chloroperbenzoic acid, hydrogen peroxide, NaIO 4 , KMnO 4 , PhICl 2 or t-BuOCl to give a sulfoxide or sulfone.
  • an oxidation reagent such as for example m-Chloroperbenzoic acid, hydrogen peroxide, NaIO 4 , KMnO 4 , PhICl 2 or t-BuOCl to give a sulfoxide or sulfone.
  • Example 1 3-(4-chlorobenzoyl)-6-hydroxy-5-isopropyl-2-methylbenzonitrile
  • Cuprous cyanide (71 mg, 0.8 mmol) was added to a solution of (4-chlorophenyl)(4-hy- droxy-5-isopropyl-2-methylphenyl)methanone (150 mg, 0.4 mmol) in anhydrous DMF (2mL) under an argon atmosphere.
  • the reaction mixture was refluxed for four hours and cooled down to 7O 0 C.
  • Ferric chloride 260 mg, 1.6 mmol was added and the mixture stirred for 30 minutes.
  • Trimethylsilyl azide (52 ⁇ L, 0.4 mmol) was added to a solution of 3-(4-chlorobenzoyl)-6- hydroxy-5-isopropyl-2-methylbenzonitrile (40 mg, 0.13 mmol) and n-dibutyltin oxide (10 mg, 0.04 mmol) in toluene (2mL).
  • the reaction vessel was flushed with argon, sealed and stirred for four days at 100 0 C.
  • the solvent was evaporated under reduced pressure and the crude mixture purified on silica gel using a gradient of ethyl acetate /heptane.
  • the titled compound was isolated in 1.6 mg (3%) yield as well as 3-(4-chlorobenzoyl)-6-hydroxy-5- isopropyl-2-methylbenzamide (Example 4, see below).
  • Transfected L(tk) cells stably expressing human GlyR ⁇ l homomers were incubated at 37 0 C (5% CO 2 ) in tissue flasks (Costar) containing Modified Eagle Medium + Earles + L- glutamin (MEM; GibcoBRL) supplemented with 10 % heat-inactivated fetal calf serum, 100 IU/ml Penicillin/Streptomycin (GibcoBRL). Cells were split twice weekly, using mild trypsination. The cells were split and seeded in 50 mm cell culture dishes 24-48 h prior to the experiment.
  • Glycine receptor-mediated whole-cell currents were recorded under voltage-clamp conditions. Borosilicate glass pipettes (GC 150- 1O 5 Clark Electromedical Instruments) were used. The cell culture dish was fitted with an inset giving a recording chamber volume of 0.6 ml. The chamber was continuously perfused with extracellular solution (see below) at ⁇ 1.5 ml/min. Test compounds were delivered by a DAD- 12 superfusion system (Adams & List Associates, Ltd, Westbury, NY; USA). The signals were recorded using an Axopatch 200A amplifier, a Digidata interface and the pClamp software (all from Axon Instruments, Foster City, CA). No series resistance compensation was used. AU experiments were performed at room temperature.
  • Glycine (Sigma) stock solution was prepared fresh each day in extracellular solution.
  • the test compounds were dissolved in DMSO to a concentration of 20 mM and diluted in the extracellular solution to the final concentration.
  • the concentration-response curve was obtained by first applying a 40 ⁇ M control concentration of glycine for 10 seconds.
  • the low- est concentration of test compound was subsequently applied for 10 seconds alone, then co-applied with 40 ⁇ M glycine for 10 seconds. This sequence was repeated with 4 concen- trations of test compound on each cell. There was no washout of compound between concentrations.
  • Typical IC 50 values for the compounds of the present invention are in the range of about 0.1 to about 1,000,000 nM. Other values for IC 50 are in the range of about 1 to about io 100,000 nM. Further values for IC 50 are in the range of about 10 nM to about 30,000 nM
  • FCA Freund's complete adjuvant
  • FCA lmg/mL
  • Rats are injected orally, subcutaneously or intraperitonealy depending on kinetic profile of the test substance. The time between administration and videotaping is also dependant on the kinetics of the test compound.
  • Rats Male Sprague-Dawley (HsdrSD) rats (Charles River, St Constant, Canada) weighing approximately 100-150 g are ordered for surgery. Rats are housed in groups of 7-9 in a tem- perature controlled room (22+1.5°C, 30-80% humidity, 12h light/dark cycle). Rats are acclimatized in the animal facility for at least one-day prior to use. Experiments are performed during the light phase of the cycle, rooms are illuminated at 300 lux intensity. Animals have food and water ad libitum.
  • a dorsal mid-line incision are made approximately from the lower lumbar (L3) level to sacral (S2) level allowing exposure of the muscles.
  • the left paraspinal muscles are isolated and removed from the L4 spinous level to the sacrum S 1 level.
  • the bone, L6 transverses process is then removed to allow easy access to the L5 spinal nerve.
  • the left L5 and L6 spinal nerves are carefully isolated and tightly ligated with 4-0 silk threads whereas L4 is "tickled" about 10 times using glass hook.
  • the incision is closed in layers using an appropriate suture material. Rats are allowed to recuperate until post-operative day 10 at which time testing can begin.
  • Rats are placed on a grid floor, and are covered by a reversed small animal cage.
  • baseline measurements are determined by touching the treated paw with a series of monofilaments of incremental stiffness in the "up/down" method (Chaplan et al. (1994)).
  • rats are randomized in homogeneous groups before experiments are started. Rats having mechanical threshold higher than 5 g are exclude from the study.
  • Rats are injected orally, subcutaneously or intraperitonealy depending on kinetic profile of the test substance. The time between administration and videotaping is also dependant on the kinetics of the test compound.

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Abstract

L'invention concerne un composé de formule (I) ou des sels associés acceptables pharmaceutiquement, dans laquelle X est sélectionné parmi l'hydrogène, halo, -CN, -CONH2, -CON(C1-6alkyl)H, -CON(C1-6alkyl)2 et des groupes hétérocycliques; R1 est sélectionné parmi C1-6alkyle et C3-6cycloalkyle; où Z représente -OH, M est sélectionné parmi C(O)-, -CH(ORa), N(Ra), et S(O)r-, où Ra représente l'hydrogène ou C1-6alkyle et r est égal à 0, 1 ou 2, R2 est sélectionné parmi C1-6alkyle, C3-6cycloalkyle, un hétérocycloalkyle, un aryle, un alkylaryle, et un hétéroaryle, R2 est substitué par halo, -NO2, -CN, -OH, -CF3, -OCF3, -NH2, et/ou -CONH2, lorsque Y représente -C1-6alkyle; ou Z représente -C1-6alkoxy, M désigne une liaison, R2 est sélectionné parmi C1-6alkyle, C3-6cycloalkyle, un hétérocycloalkyle, un aryle, un alkylaryle, et un hétéroaryle, lorsque Y désigne -C1-6alkoxy.
EP06733400A 2005-05-09 2006-05-08 Nouveaux composes i Withdrawn EP1881950A1 (fr)

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